Methods for improving vision

ABSTRACT

The present invention is directed to methods for improving night vision and visual performance in low light conditions comprising ophthalmological administration of compositions comprising low dose brimonidine and a vehicle for improved performance.

FIELD OF THE INVENTION

The present invention relates to methods for improving night vision andvisual performance in low light conditions comprising ophthalmologicaladministration of compositions comprising low dose brimonidine and avehicle for improved performance.

BACKGROUND OF THE INVENTION

Glare and halo have long been known to be associated with opticalimperfections of the cornea, particularly spherical aberrations. Nightvision is particularly sensitive to such aberrations, where a peripheralring of cornea does not have the same focal point as the sharper acuitycentral corneal zones, resulting in haloing. Other aberrations includecoma and together these aberrations additionally cause streaking oflight, and glare. Studies on subjects under conditions of increasedpupil size such as cloudy days or suboptimal indoor lighting increasedaberrations and can cause a large reduction in contrast acuity. Increasein pupil area of as little as 10 mm² has been associated with reducedvisual performance, increased fatigue, and may also adversely affectsports performance. Taken to an extreme, such as under conditions ofpharmacologic dilation, even daytime driving performance deteriorates,including but not limited to gap perception and road sign distancedeterioration. Boyce, P R et al., The impact of spectral powerdistribution on the performance of an achromatic visual task, LightingResearch and Technology, Jun. 1, 2003; Pupil dilatation does affect someaspects of daytime driving performance. Br J Ophthalmol, 2003 Nov:87(11): 1387-90.

Corneal and cataract surgery may induce spherical aberrations similarlyreducing vision and vision performance, particularly in reduced lightingconditions such as night driving. Radial keratotomy, automated lamellarkeratoplasty, and more recently laser vision correction have beendemonstrated to, in some cases, induce spherical aberration and otherhigher order optical aberrations, as may cataract surgery. As little as0.5 mm reduction in pupil size significantly reduces sphericalaberration in almost all cases, as these aberrations are most severenear the margins of the scotopic pupil, as they are inverselyproportional to optical zone size.

A further issue is reduced vision in low light conditions. For example,under conditions where luminance is below 500 candela per square metervisual acuity is reduced. These low light conditions may occur indoorsor outdoors and can affect performance in a variety of tasks such aswork and sports.

It is possible to pharmacologically modify the pupil and improve vision.This improvement can be measured either indirectly as a reduction inSnellen acuity (high contrast) or more commonly reduction in lowcontrast acuity (mesopic or scotopic). This improvement can also bemeasured more directly as a reduction in aberrations via wave frontaberrometry, which allows quantifying the aberrations themselves.Historically, miotics have been used to reduce pupil size, and therebyfilter out peripheral corneal, corneal inlay, lenticular, or lensimplant induced (post cataract surgery) aberrations. Dilute miotics,such as pilocarpine and aceclidine, along with brimonidine typically0.15% to 0.20% have been used to effect pupil size reduction anddocumented improvement in night vision. Miotics are difficult to use forthis purpose, causing ciliary pain, tachyphylaxis, some induced myopiadepending on concentration used, and may cause undesirable dimming fromexcessive peak constriction.

Thus, there is a need in the art for a method of improving visionwithout the attendant side effects.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to a method ofimproving night vision comprising administering to an eye of subject inneed thereof a composition comprising from about 0.01% to about 0.05%w/v brimonidine, from about 1% to about 5% w/v of a nonionic surfactantand a viscosity enhancer, wherein the composition has a pH from about6.0 to about 8.0.

In one embodiment, the present invention is directed to a method ofimproving sports performance under a luminance level below 500 candelaper square meter (“cd/m²”) comprising administering to an eye of subjectin need thereof a composition comprising from about 0.01% to about0.050% w/v brimonidine, from about 1% to about 5% w/v of a nonionicsurfactant and a viscosity enhancer, wherein the composition has a pHfrom about 6.0 to about 8.0.

In one embodiment, the present invention is directed to a method ofimproving eye fatigue under a luminance level below 500 cd/m² comprisingadministering to an eye of subject in need thereof a compositioncomprising from about 0.01% to about 0.050% w/v brimonidine, from about1% to about 5% w/v of a nonionic surfactant and a viscosity enhancer,wherein the composition has a pH from about 6.0 to about 8.0.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention is directed to a method ofimproving night vision comprising administering to an eye of subject inneed thereof a composition comprising from about 0.01% to about 0.05%w/v brimonidine, preferably from about 0.015% to about 0.040% w/v, fromabout 1% to about 5% w/v of nonionic surfactant, preferably selectedfrom the group consisting of a polysorbate, a poloxamer, a polyoxyl, analkyl aryl poly ether, a cyclodextrin and a tocopheryl polyethyleneglycol succinate, more preferably a polysorbate, even more preferablypolysorbate 80 and a viscosity enhancer, preferably selected fromhydroxypropylmethyl cellulose and carboxymethyl cellulose, preferably ata concentration from about 0.1% to about 2% w/v, more preferably fromabout 1.0% to about 1.25% w/v, optionally, from about 0.1% to about 5%w/v mannitol, optionally, from about 1 to about 10 millimolar boric acidand optionally, from about 0.05% to about 0.5% w/v sorbate, wherein thecomposition has a pH from about 6.0 to about 8.0.

In one embodiment, the present invention is directed to a method ofimproving sports performance or reduce eye fatigue under a luminancelevel below 500 cd/m²), preferably below 10 cd/m² and more preferablybelow 1×10⁻³ cd/m², comprising administering to an eye of subject inneed thereof a composition comprising from about 0.01% to about 0.05%w/v brimonidine, preferably from about 0.015% to about 0.040% w/v, fromabout 1% to about 5% w/v of nonionic surfactant, preferably selectedfrom the group consisting of a polysorbate, a poloxamer, a polyoxyl, analkyl aryl poly ether, a cyclodextrin and a tocopheryl polyethyleneglycol succinate, more preferably a polysorbate, even more preferablypolysorbate 80 and a viscosity enhancer, preferably selected fromhydroxypropylmethyl cellulose and carboxymethyl cellulose, preferably ata concentration from about 0.1% to about 2% w/v, more preferably fromabout 1.0% to about 1.25% w/v, optionally, from about 0.1% to about 5%w/v mannitol, optionally, from about 1 to about 10 millimolar boric acidand optionally, from about 0.05% to about 0.5% w/v sorbate,

wherein the composition has a pH from about 6.0 to about 8.0.

In one embodiment, the present invention is directed to a method ofimproving eye fatigue under a luminance level below 500 cd/m²,preferably below 100 cd/m² and more preferably below 10 cd/m² and evenmore preferably below 1×10⁻³ cd/m² comprising administering to an eye ofsubject in need thereof a composition comprising from about 0.01% toabout 0.050% w/v brimonidine, preferably from about 0.015% to about0.040% w/v, from about 1% to about 5% w/v of nonionic surfactant,preferably selected from the group consisting of a polysorbate, apoloxamer, a polyoxyl, an alkyl aryl poly ether, a cyclodextrin, atocopheryl polyethylene glycol succinate. a glucosyl dialkyl ethers anda crown ether, ester-linked surfactants, more preferably a polysorbate,even more preferably polysorbate 80 and a viscosity enhancer, preferablyselected from hydroxypropylmethyl cellulose and carboxymethyl cellulose,preferably at a concentration from about 0.1% to about 2% w/v, morepreferably from about 1.0% to about 1.25% w/v, optionally, from about0.1% to about 5% w/v mannitol, optionally, from about 1 to about 10millimolar boric acid and optionally, from about 0.05% to about 0.5% w/vsorbate,

wherein the composition has a pH from about 6.0 to about 8.0.

In a more preferred embodiment, administration of compositions of thepresent invention occurs once or twice daily.

In another more preferred embodiment, administration of compositions ofthe present invention once or twice daily provides improvement of nightvision that occurs for at least four weeks without tachyphylaxis.

In another more preferred embodiment, administration of compositions ofthe present invention provides a reduction in the diameter of the pupilof the eye of the subject by 0.5 millimeters or more for 6 or morehours.

Compositions of the present invention have a pH from about 6.0 to about8.0, preferably from about 6.5 to about 7.5 and most preferably about7.5

The term “brimonidine” encompasses, without limitation, brimonidinesalts and other derivatives, and specifically includes, but is notlimited to, brimonidine tartrate,5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, Alphagan®(Alphagan is a registered trademark of Allergan, Inc.), and UK14,304.

Brimonidine may be present in compositions of the present invention at aconcentration from about 0.01% to about 0.050% w/v, from about 0.02% toabout 0.045% w/v or from about 0.015% to about 0.040% w/v.

Polysorbates suitable for use in the present invention include, but arenot limited to, polysorbate 20 (polyoxyethylene (20) sorbitanmonolaurate), polysorbate 40 (polyoxyethylene (20) sorbitanmonopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitanmonostearate) and polysorbate 80 (polyoxyethylene (20) sorbitanmonooleate.

Cyclodextrins suitable for use in the present invention include, but arenot limited to, ionically charged (e.g. anionic) beta—cyclodextrins withor without a butyrated salt (Captisol®) 2-hydroxypropyl betacyclodextrin (“HPβCD”), alpha cyclodextrins and gamma cyclodextrins.

Poloxamers include but are not limited to poloxamer 103, poloxamer 123,and poloxamer 124, poloxamer 407, poloxamer 188, poloxamer 338 and anypoloxamer analogue or derivative.

Polyoxyls include but are not limited to Brij® 35, 78, 98, 700(polyoxyethylene glycol alkyl ethers) and Spans (sorbitan esters) andSpan® 20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, and sorbitan monooleate).

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 5% w/v” is to be understood as“4.5% to 5.5% w/v.” Therefore, amounts within 10% of the claimed valueare encompassed by the scope of the claims.

As used herein “% w/v” refers to the percent weight of the totalcomposition.

As used herein, the term “administration” or “administering” refers totopical application, injection or administration via implants.

The articles “a,” “an” and “the” are intended to include the plural aswell as the singular, unless the context clearly indicates otherwise.

EXAMPLE 1 (VIRTUAL) Methods

Ten subjects were administered one to two drops daily of eachcomposition of Table 1, below for a four-week period. If a subject wasadministered more than one composition, then that subject has a one-weekwashout period following the last administration of the priorcomposition. Each of the ten subjects were required to (1) experienceglare halo, 2) have high spherical aberration as detected by a wavefrontaberrometer and 3) have a positive light flash test. A positive lightflash test consists of improvement in contralateral eye when a pen lightis used to illuminate the opposite eye.

TABLE 1 Miosis following instillation of brimonidine compositionsComposition 1 2 3 4 5 Brimonidine 0.015% 0.025% 0.035% 0.040% 0.040%Polysorbate 80 — — 1.00% 2.00% 2.00% Poloxamer 407 — — 1.00% 0.50% —Poloxamer 188 — — 0.20% 0.50% — HPγCD — — 1.50% — — Polyoxyl Castor Oil— — 0.015% — — Mannitol — — 1.00% 0.50% 0.50% NaCl 0.09% 0.09% 0.40%0.40% 0.40% HPMC or CMC — — 0.50% 1.20% 1.20% BAK 0.01% 0.01% 0.01%0.01% 0.01% Boric acid — — 4 mM 5 mM 5 mM pH 6.5 7.0 7.5 7.5 7.5 ResultsWeeks of peak miosis 3 ≥4 ≥4 ≥4 — Average miosis 1.0 1.0 1.2 1.4 —(during weeks of peak miosis, millimeters) Miosis range (millimeters)0.5-1.5 0.5-1.5 0.7-2.0 0.8-2.2 — Duration of peak 4 4 4.5 5 — miosisfollowing instillation (hours) Whitening 2 3 3.2 3.5 — (0-4, 4 best)Hyperemia Yes No No No —“peak miosis” is the maximum miosis achieved upon instillation of thecomposition, which for composition 1 is expected to be of limited numberof days due to a rebound effect.“>4” denotes peak miosis was achieved for at least 4 weeks and ispredicted to not be limited to a particular number of days.

Results

Each subject administered composition 1 experienced only three weeks orless of peak miosis. Further, subjects administered composition 1experienced eye redness (i.e. hyperemia) due to the relatively high doseof brimonidine. However, subjects administered composition 2 continuedto experience peak miosis at the end of the four-week study and none ofthese subjects experienced hyperemia. Further miosis, whitening andduration of peak miosis following instillation improved when low dosebrimonidine was formulated in compositions of the present invention.

EXAMPLE 2 (VIRTUAL)

10 nonpresbyopic (ages 25-39) subject were exposed to a 100-lumen indoorambient light with their BCDA (corrected distance acuity). On separatedays at the same time of day the subjects have their reading speedmeasured and averaged for each of baseline and after instillation ofcompositions 1-5 from Table 1, above. Subjects were then asked to ratetheir eye fatigue after 20 minutes of consecutive reading of writtenmaterial.

TABLE 2 Eye fatigue, reading speed and pupil size following instillationof a composition of the present invention Composition none 1 2 3 4 5Reading 50.0 50.3 50.5 50.7 50.9 51.1 speed (wpm) Pupil 3.3 3.1 2.902.70 2.55 2.40 size (mm) Pupil 10.89 9.61 8.41 7.29 6.50 5.29 area (mm²)Pupil size — 1.28 2.48 3.60 4.39 5.60 difference vs. baseline (mm²) Eyefatigue 2.0 1.8 1.6 1.4 1.20 1.0 0-5) % Relief eye — 10% 20% 30% 40% 50%fatigue

Following instillation of compositions 1 -5, subjects experiencedreduction in eye fatigue proportional to the reduction in the size oftheir pupil (i.e. from 10% to 50%).

What is claimed is:
 1. A method of reducing eye fatigue from indoorlighting under a luminance level below 500 candelas per square meter(cd/m²) comprising administering to an eye of subject in need thereof acomposition comprising from about 0.01% to about 0.05% w/v brimonidine,from about 1% to about 5% w/v of a nonionic surfactant and a viscosityenhancer, wherein w/v denotes weight by total volume of the compositionand wherein the composition has a pH from about 6.0 to about 8.0.
 2. Themethod of claim 1, wherein brimonidine is at a concentration from about0.025% to about 0.05% w/v.
 3. The method of claim 1, wherein thenonionic surfactant is selected from the group consisting of apolysorbate, a poloxamer, a polyoxyl, an alkyl aryl poly ether, acyclodextrin, a tocopheryl polyethylene glycol succinate and acombination thereof.
 4. The method of claim 3, wherein the nonionicsurfactant is a polysorbate.
 5. The method of claim 4, wherein thepolysorbate is polysorbate 80 and the viscosity enhancer is selectedfrom hydroxypropyl methyl cellulose and carboxymethyl cellulose at aconcentration from about 0.1% to about 2% w/v.
 6. The method of claim 1,further comprising from about 0.1% to about 5% w/v mannitol.
 7. Themethod of claim 6, wherein the viscosity enhancer is from about 1.0% toabout 1.25% w/v hydroxypropyl methyl cellulose.
 8. The method of claim7, wherein the composition further comprises from about 1 to about 10millimolar boric acid and from about 0.05% to about 0.5% w/v sorbate. 9.The method of claim 1, wherein administration occurs once or twicedaily.
 10. The method of claim 9, wherein the reduction of eye fatigueoccurs for at least four weeks without tachyphylaxis.
 11. The method ofclaim 1, wherein a pupil of the eye of the subject is reduced diameterby 0.5 millimeters or more for 6 or more hours.
 12. The method of claim1, wherein the luminance levels is below 10 cd/m².
 13. The method ofclaim 12, wherein the luminance level is below 1×10⁻³ cd/m².